Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis

Cardiac mitochondrial function is altered in a variety of inherited and acq uired cardiovascular diseases. Recent studies have identified the transcrip tional coactivator peroxisome proliferator-activated receptor gamma coactiv ator-1 (PGC-1) as a regulator of mitochondrial function in tissues speciali zed for thermogenesis, such as brown adipose. We sought to determine whethe r PGC-1 controlled mitochondrial biogenesis and energy-producing capacity i n the heart, a tissue specialized for high-capacity ATP production. We foun d that PGC-1 gene expression is induced in the mouse heart after birth and in response to short-term fasting, conditions known to increase cardiac mit ochondrial energy production. Forced expression of PGC-1 in cardiac myocyte s in culture induced the expression of nuclear and mitochondrial genes invo lved in multiple mitochondrial energy-transduction/energy-production pathwa ys, increased cellular mitochondrial number, and stimulated coupled respira tion. Cardiac-specific overexpression of PGC-1 in transgenic mice resulted in uncontrolled mitochondrial proliferation in cardiac myocytes leading to loss of sarcomeric structure and a dilated cardiomyopathy. These results id entify PGC-1 as a critical regulatory molecule in the control of cardiac mi tochondrial number and function in response to energy demands.